Search

Purpose:Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.Experimental Design:Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set.Results:Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression.Conclusions:Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.

Supplementary Figure from Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception

Supplementary Data from Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception

PURPOSE We determined whether a large, multianalyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS We defined a biologically relevant subspace of blood analytes on the basis of previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, and 182 early-stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects on the basis of their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects. RESULTS A classification model was trained on 669 subjects (358 healthy, 159 benign, and 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, and 30 early-stage PDAC) yielded an area under the receiver operating characteristic curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC versus healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease and 73 early- and late-stage PDAC cases) and 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC versus healthy controls. CONCLUSION Individually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.

The confounding effects of next-generation sequencing (NGS) noise on detection of low frequency circulating tumor DNA (ctDNA) without a priori knowledge of solid tumor mutations has limited the applications of circulating cell-free DNA (ccfDNA) in clinical oncology. Here, we use a 118 gene panel and leverage ccfDNA technical replicates to eliminate NGS-associated errors while also enhancing detection of ctDNA from pancreatic ductal adenocarcinomas (PDACs). Pre-operative ccfDNA and tumor DNA were acquired from 14 patients with PDAC (78.6% stage II-III). Post-operative ccfDNA was also collected from 11 of the patients within 100 days of surgery. ctDNA detection was restricted to variants corresponding to pathogenic mutations in PDAC present in both replicates. PDAC-associated pathogenic mutations were detected in pre-operative ccfDNA in four genes (KRAS, TP53, SMAD4, ALK) from five patients. Of the nine ctDNA variants detected (variant allele frequency: 0.08%-1.59%), five had a corresponding mutation in tumor DNA. Pre-operative detection of ctDNA was associated with shorter survival (312 vs. 826 days; χ 2 =5.4, P = 0.021). Guiding ctDNA detection in pre-operative ccfDNA based on mutations present in tumor DNA yielded a similar survival analysis. Detection of ctDNA in the post-operative ccfDNA with or without tumor-informed guidance was not associated with outcomes. Therefore, the detection of PDAC-derived ctDNA during a broad and untargeted survey of ccfDNA with NGS may be a valuable, non-invasive, prognostic biomarker to integrate into the clinical assessment and management of patients prior to surgery.

OBJECTIVE Surgical complications have substantial impact on healthcare costs. We propose an analysis of the financial impact of postoperative complications. SUMMARY OF BACKGROUND DATA Both complications and preoperative patient risk have been shown to increase costs following surgery. The extent of cost increase due to specific complications has not been well described. METHODS A single institution's American College of Surgeons National Surgical Quality Improvement Program data was queried from 2012 to 2018 and merged with institutional cost data for each encounter. A mixed effects multivariable generalized linear model was used to estimate the mean relative increase in hospital cost due to each complication, adjusting for patient and procedure-level fixed effects clustered by procedure. Potential savings were calculated based on projected decreases in complication rates and theoretical hospital volume. RESULTS There were 11,897 patients linked between the 2 databases. The rate of any American College of Surgeons National Surgical Quality Improvement Program complication was 11.7%. The occurrence of any complication resulted in a 1.5-fold mean increase in direct hospital cost [95% confidence interval (CI) 1.49-1.58]. The top 6 most costly complications were postoperative septic shock (4.0-fold, 95% CI 3.58-4.43) renal insufficiency/failure (3.3-fold, 95% CI 2.91-3.65), any respiratory complication (3.1-fold, 95% CI 2.94-3.36), cardiac arrest (3.0-fold, 95% CI 2.64-3.46), myocardial infarction (2.9-fold, 95% CI 2.43-3.42) and mortality within 30 days (2.2-fold, 95% CI 2.01-2.48). Length of stay (6.5 versus 3.2 days, P < 0.01), readmission rate (29.1% vs 3.1%, P < 0.01), and discharge destination outside of home (20.5% vs 2.7%, P < 0.01) were significantly higher in the population who experienced complications. CONCLUSIONS Decreasing complication rates through preoperative optimization will improve patient outcomes and lead to substantial cost savings.

PurposeWe determined whether a large, multi-analyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC).Experimental DesignWe defined a biologically relevant subspace of blood analytes based on previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, 182 early stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects based on their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects.ResultsA classification model was trained on 669 subjects (358 healthy, 159 benign, 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, 30 early-stage PDAC) yielded an area under the receiver operating characteristic (ROC) curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC vs. healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease, 73 early and late stage PDAC) as well as 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC vs. healthy controls.ConclusionsIndividually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.

Value is defined as health outcomes important to patients relative to cost of achieving those outcomes: Value = Quality/Cost. For inguinal hernia repair, Level 1 evidence shows no differences in long-term functional status or recurrence rates when comparing surgical approaches. Differences in value reside within differences in cost. The aim of this study is to compare the value of different surgical approaches to inguinal hernia repair: Open (Open-IH), Laparoscopic (Lap-IH), and Robotic (R-TAPP).Variable and fixed hospital costs were compared among consecutive Open-IH, Lap-IH, and R-TAPP repairs (100 each) performed in a university hospital. Variable costs (VC) including direct materials, labor, and variable overhead ($/min operating room [OR] time) were evaluated using Value Driven Outcomes, an internal activity-based costing methodology. Variable and fixed costs were allocated using full absorption costing to evaluate the impact of surgical approach on value. As cost data is proprietary, differences in cost were normalized to Open-IH cost.Compared to Open-IH, VC for Lap-IH were 1.02X higher (including a 0.81X reduction in cost for operating room [OR] time). For R-TAPP, VC were 2.11X higher (including 1.36X increased costs for OR time). With allocation of fixed cost, a Lap-IH was 1.03X more costly, whereas R-TAPP was 3.18X more costly than Open-IH. Using equivalent recurrence as the quality metric in the value equation, Lap-IH decreases value by 3% and R-TAPP by 69% compared to Open-IH.Use of higher cost technology to repair inguinal hernias reduces value. Incremental health benefits must be realized to justify increased costs. We expect payors and patients will incorporate value into payment decisions.

Introduction: Adrenocorticotropin hormone (ACTH) secreting pancreatic neuroendocrine neoplasms (pNENs) are rare. The clinical and biological behavior of pNENs is poorly understood. Patients often present at an advanced stage of disease and outcomes remain poor. This report demonstrates a case of ectopic Cushing's syndrome secondary to an ACTH-producing pancreatic neuroendocrine carcinoma (pNEC). Case report: A 54-year-old woman presented with rapidly progressive Cushing's syndrome complicated by hypertension and acute heart failure. This was ultimately found to be secondary to a metastatic ACTH-producing pNEC. She underwent laparoscopic distal pancreatectomy and splenectomy with hepatic metastasectomy as primary treatment. She had rapid correction of her endocrine abnormalities and associated physiological abnormalities. She had progressive hepatic metastases found on imaging at 3 months, but remained free of significant endocrine abnormalities for 9 months after surgery. Her disease did recur and she died of complications associated with her disease at 1 year after her surgery. Conclusion: ACTH-producing pNEN is a very rare disease with a poor prognosis. Robust evidence to guide treatment decisions is limited. This report suggests that aggressive surgical management of primary and metastatic lesions for management of this disease is reasonable, consistent with prior case reports. Control of endocrine abnormalities offers the best opportunity for prolonged survival, and an aggressive surgical approach can achieve this goal. The patient presented had control of endocrine abnormalities after surgery for 9 months before symptomatic disease recurrence.

Background Utilization of multimodality therapy for clinical stage I-II pancreatic ductal adenocarcinoma is associated with meaningful prolongation of survival. Although the qualitative existence of disparities in treatment utilization by socioeconomic status and race/ethnicity is well documented, the absolute magnitudes of these disparities have not been previously quantified. Methods The exposures in this retrospective cohort study of the 2010–2015 National Cancer Database were a 7-value area-level socioeconomic status index and race/ethnicity. Main outcomes were surgery, chemotherapy, and multimodality therapy (surgery and chemotherapy). Adjusted rate differences were calculated after logistic regression. Models excluded intermediate variables. Overall survival was evaluated in unadjusted and adjusted analyses. Results Of 43,760 patients, 63.4% underwent surgery. Of 39,808 patients without chemotherapy contraindications, refusal, or missing data, 75.1% received chemotherapy and 51.4% received multimodality therapy. Adjusted rate differences for utilization of surgery, chemotherapy, and multimodality therapy in the lowest socioeconomic status patients were –10.0 (95% confidence interval [CI] –12.4 to –7.5), –12.7 (95% CI –16.3 to –9.1), and –15.4 (95% CI –18.8 to –12.0), respectively, versus the highest socioeconomic status patients. Adjusted rate differences for multimodality therapy utilization in non-Hispanic Black and Hispanic patients were –10.1 (95% CI –13.6 to –6.7) and –11.8 (95% CI –14.3 to –9.2), respectively, versus non-Hispanic White patients. Median overall survival increased in a graded fashion from 14.1 (95% CI 13.4–14.8) months in the lowest socioeconomic status patients to 20.2 months (95% CI 19.6–20.8) in the highest socioeconomic status patients. Survival differences were attenuated but not eliminated in multivariable Cox models. Conclusion Socioeconomic status and race/ethnicity are more powerful determinants of whether patients receive treatment for clinical stage I-II pancreatic ductal adenocarcinoma than previously appreciated. Nationwide quality improvement efforts aimed at addressing these inequities are warranted.

Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Experimental Design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.

To (1) evaluate rates of surgery for clinical stage I-II pancreatic ductal adenocarcinoma (PDAC), (2) identify predictors of not undergoing surgery, (3) quantify the degree to which patient- and hospital-level factors explain differences in hospital surgery rates, and (4) evaluate the association between adjusted hospital-specific surgery rates and overall survival (OS) of patients treated at different hospitals.Curative-intent surgery for potentially resectable PDAC is underutilized in the United States.Retrospective cohort study of patients ≤85 years with clinical stage I-II PDAC in the 2004 to 2014 National Cancer Database. Mixed effects multivariable models were used to characterize hospital-level variation across quintiles of hospital surgery rates. Multivariable Cox proportional hazards models were used to estimate the effect of adjusted hospital surgery rates on OS.Of 58,553 patients without contraindications or refusal of surgery, 63.8% underwent surgery, and the rate decreased from 2299/3528 (65.2%) in 2004 to 4412/7092 (62.2%) in 2014 (P0.001). Adjusted hospital rates of surgery varied 6-fold (11.4%-70.9%). Patients treated at hospitals with higher rates of surgery had better unadjusted OS (median OS 10.2, 13.3, 14.2, 16.5, and 18.4 months in quintiles 1-5, respectively, P0.001, log-rank). Treatment at hospitals in lower surgery rate quintiles 1-3 was independently associated with mortality [Hazard ratio (HR) 1.10 (1.01, 1.21), HR 1.08 (1.02, 1.15), and HR 1.09 (1.04, 1.14) for quintiles 1-3, respectively, compared with quintile 5] after adjusting for patient factors, hospital type, and hospital volume.Quality improvement efforts are needed to help hospitals with low rates of surgery ensure that their patients have access to appropriate surgery.

Background Significant overtreatment of intraductal papillary mucinous neoplasms can be attributed to low specificity of the current International Consensus Guidelines as well as nonconformity with the guidelines. We compare the ability of the 2012 and revised 2017 intraductal papillary mucinous neoplasms International Consensus Guidelines to predict high-grade dysplasia/invasive cancer and to determine the preoperative variables that predict resection of benign or low-grade dysplasia in tertiary care centers. Methods Clinical, radiographic, and pathologic data for resected intraductal papillary mucinous neoplasms at 3 high-volume National Cancer Institute Cancer Centers were reviewed and the 2012 and 2017 consensus criteria were retrospectively applied. When International Consensus Guidelines were not met, clinical decision analysis was used to determine the primary indication for resection. Logistic regression identified variables associated with pathologic grade. Results Records for a total of 251 patients were reviewed, 129 of whom (52%) had low-grade dysplasia. The revised 2017 International Consensus Guidelines had high sensitivity (98.4%) and negative predicted value (96.1%), and all high-risk stigmata predicted high-grade dysplasia/invasive cancer; however, specificity remained low (14.8%). Nonconformity with International Consensus Guidelines was the most powerful predictor of low-grade dysplasia on final pathologic examination (9.5; 2.12–40.78). Independent predictors of low-grade dysplasia included age younger than 50 (2.46; 1.08–5.62), fine-needle aspiration without epithelial cells (2.6; 1.43–4.72), and normal duct diameter (3.07; 1.99–4.75). Diabetes developed in 30% of patients after resection. Conclusion Management of intraductal papillary mucinous neoplasms remains clinically challenging. Low specificity of the International Consensus Guidelines and nonconformity with the guidelines continue to contribute to unnecessary pancreatic resections. Improved tools for disease classification as well as a better understanding of the natural history, biology, and rates of progression of intraductal papillary mucinous neoplasms are needed to avoid surgical overtreatment of low-grade intraductal papillary mucinous neoplasms.

Background Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery. Methods The 2004–2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I–II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1–14 days), medium (15–42), and long (43–120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models. Results Of 16,763 patients, time-to-surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time-to-surgery patients were young, privately insured, healthy, and treated at low-volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short. Conclusion In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe.

The size and importance of socioeconomic status (SES)-based disparities in use of surgery for non-advanced stage gastrointestinal (GI) cancers have not been quantified. The exposure in this study of patients age 18–80 with one of nine non-advanced stage GI cancers in the 2007–2015 SEER database was a census tract-level SES composite. Multivariable models assessed associations of SES with use of surgery. Causal mediation analysis was used to estimate the proportion of survival disparities in SES quintiles 1 versus 5 that were mediated by disparities in use of surgery. Lowest SES quintile patients underwent surgery at significantly lower rates than highest quintile patients in each cancer. SES-based disparities in use of surgery were large and graded in esophagus adenocarcinoma, intrahepatic and extrahepatic cholangiocarcinoma, and pancreatic adenocarcinoma. Smaller but clinically relevant disparities were present in stomach, ampulla, and small bowel adenocarcinoma, whereas disparities were small in colorectal adenocarcinoma. Five-year all-stage overall survival (OS) was correlated with the size of disparities in use of surgery in SES quintiles 1 versus 5 (r = − 0.87; p = 0.003). Mean OS was significantly longer (range 3.5–8.9 months) in SES quintile 5 versus 1. Approximately one third of SES-based survival disparities in poor prognosis GI cancers were mediated by disparities in use of surgery. The size of disparities in use of surgery in SES quintiles 1 versus 5 was correlated with the proportion mediated (r = 0.98; p

OBJECTIVE The aim of the study was to describe county-level variation in use of surgery for stage I-II pancreatic ductal adenocarcinoma (PDAC) and the association between county surgery rates and cancer-specific survival (CSS). BACKGROUND The degree of small geographic area variation in use of surgery for stage I-II PDAC and the association between area surgery rates and CSS remain incompletely defined. METHODS This is a retrospective cohort study of patients aged 18 to 80 years in the 2007 to 2015 Surveillance, Epidemiology, and End Results database with stage I-II PDAC without contraindications to surgery or refusal. Multilevel models were used to characterize county-level variation in use of surgery and CSS. County-specific risk- and reliability-adjusted surgery rates and CSS rates were calculated. RESULTS Of 18,100 patients living in 581 counties, 10,944 (60.5%) underwent surgery. Adjusted county-specific surgery rates varied 1.5-fold from 49.9% to 74.6%. Median CSS increased in a graded fashion from 13 months [interquartile range (IQR) 13-14] in counties with surgery rates of 49.9% to 56.9% to 18 months (IQR 17-19) in counties with surgery rates of 68.0% to 74.6%. Results were similar in multivariable analyses. Adjusted county 18-month CSS rates varied 1.6-fold from 32.7% to 53.7%. Adjusted county surgery and 18-month CSS rates were correlated (r = 0.54; P < 0.001) and county surgery rates explained approximately half of county-level variation in CSS. Only 18 (3.1%) counties had adjusted surgery rates of 68.0% to 74.6%, which was associated with the longest CSS. CONCLUSIONS County-specific rates of surgery varied substantially, and patients living in areas with higher surgery rates lived longer. These data suggest that increasing use of surgery in stage I-II PDAC could lead to improvements in survival.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC.

419 Background: A role for the immune system in predicting treatment outcomes in PDA has not been well-studied prospectively, especially in the curative setting. Here, we investigated the capacity of two established chemotherapy regimens to trigger an immune response against PDA when administered as neoadjuvant therapy. Methods: We used available PDA surgical specimens from SWOG S1505 (a randomized phase II trial of perioperative chemotherapy with either mFOLFIRINOX [FFX] or gemcitabine/nab-paclitaxel [GA] for resectable PDA; ASCO 2020 abstr 4504) resected after 3 months of neoadjuvant chemotherapy, and matched untreated controls from the biorepository at the University of Utah. Multiplex immunohistochemistry (IHC) for CD8, CD68, CK19, FOXP3, PDL1, CD3, and Ki67 was performed; regions of interest (ROIs) were transcribed by a central pathologist. ROIs were digitally quantified using custom image analysis algorithms created using Visiopharm Integrator System software to detect and classify cells within superimposed grids for quantification; medians and coefficients of variation (CV) were calculated. Wilcoxon signed-rank test and Cox regression models were used to analyze associations between IHC cell counts and pathologic response (pR) and overall survival (OS), respectively. Results: IHC cell counts varied between treated (Rx) (n = 57; FFX = 34, GA = 23) and control (C) (n = 61) specimens for: CK19 percent area was 7.9 vs 15.6 (p < 0.001); total Ki67/mm2 was 211 vs 400 (p < 0.001); total CD3/mm2 was 376 vs 676 (p < 0.001); Foxp3/mm2 was 81.5 vs 152.8 (p < 0.001); CD8/mm2 was 313 vs 477 (p < 0.001); CD68/mm2 was 507 vs 741 (p = 0.015). PDL1 expression was undetectable in the majority of specimens, both Rx and C. FFX (vs GA) was associated with fewer CK19+Ki67+ cells (459 vs 1026, p = 0.017) but more CD68+ cells (33,241 vs 13,334, p = 0.007) and slightly more CD8+ cells (19,809 vs 14,344, p = 0.049). In all Rx patients, complete/major (n = 19) vs poor/no (n = 36) pR was associated with total CD3/mm2: 461 vs 308 (p = 0.019); the other parameters showed no notable differences. OS showed no remarkable associations with the tested parameters. Conclusions: We have demonstrated: 1) Decreased tumor cells and proliferating cells in Rx vs C samples, as expected. This decrease is more pronounced with FFX compared with GA; 2) Decreased total CD3+ T cells as well as regulatory Foxp3+ T cells in Rx vs C samples, which is unexpected; 3) A reduction in CD68+ myeloid cells in Rx vs C samples, which is expected but more pronounced with GA compared with FFX; 4) Rx samples did not show an increased expression of PDL1, compared with C; and 5) Improved pR was associated with increased T cell infiltrate, pointing toward a possible mechanism. Together, these data support the capacity of neoadjuvant chemotherapy to modulate the immune response to PDA. Therapeutic implications of such changes merit further investigation. Clinical trial information: NCT02562716.

Although B cell response is frequently found in cancer, there is little evidence that it alters tumor development or progression. The process through which tumor-associated antigens trigger humoral response is not well delineated. We investigate the repertoire of antigens associated with humoral immune response in pancreatic ductal adenocarcinoma (PDAC) using in-depth proteomic profiling of immunoglobulin-bound proteins from PDAC patient plasmas and identify tumor antigens that induce antibody response together with exosome hallmark proteins. Additional profiling of PDAC cell-derived exosomes reveals significant overlap in their protein content with immunoglobulin-bound proteins in PDAC plasmas, and significant autoantibody reactivity is observed between PDAC cell-derived exosomes and patient plasmas compared to healthy controls. Importantly, PDAC-derived exosomes induce a dose-dependent inhibition of PDAC serum-mediated complement-dependent cytotoxicity towards cancer cells. In summary, we provide evidence that exosomes display a large repertoire of tumor antigens that induce autoantibodies and exert a decoy function against complement-mediated cytotoxicity.

This population-based study investigates the survival and causes of death in patients with pancreatic adenocarcinoma to 21 years after diagnosis.

Background Genes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history. Methods Preliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS). Results Approximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS. Conclusion With the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures. Electronic supplementary material The online version of this article (10.1186/s12885-018-4573-5) contains supplementary material, which is available to authorized users.

Single-center studies in pancreatic adenocarcinoma have suggested that preoperative chemotherapy (PCT) is associated with higher lymph node ratio (LNR) than preoperative chemoradiation (PCRT). The association of postoperative chemotherapy with overall survival (OS) in patients treated with PCT and PCRT remains unclear. Our objectives were to investigate whether (1) PCT is associated with higher LNR than PCRT and (2) postoperative chemotherapy is associated with longer OS after PCT and PCRT in LNR-stratified cohorts. A retrospective cohort study was performed of patients with pancreatic adenocarcinoma treated with PCT or PCRT followed by resection between 2006 and 2014 in the National Cancer Database. Temporal trends were evaluated with Cuzick’s test. OS was evaluated with multivariable Cox regression and inverse probability weighted (IPW) Cox regression. Of 4187 patients, 1993 (47.6%) received PCT. PCT rates were stable at approximately 30% in 2006–2010 (p = 0.33) but increased to 64.9% by 2014 (p

Background: Several retrospective studies suggest that perioperative care and anesthetic management for cancer resection may influence cancer recurrence or patient survival. Various intraoperative techniques such as paravertebral blocks, decreased opioid use, immunomodulation, and perioperative antiinflammatory administration, have previously been assessed for improved patient survival. The aim of this study was to assess associations between perioperative management and survival in patients undergoing resection of pancreatic adenocarcinoma. Methods: Survival data and anesthetic records for 144 patients who had surgical resection of pancreatic adenocarcinoma from 2001 to 2012 were obtained and associations were sought between survival and 19 predefined variables. The authors performed a propensity weighted multivariable statistical analysis using Cox proportional hazards. Results: Median length of survival was 562 days with 95% confidence interval (471, 680). In a multivariable Cox proportional hazard model of survival, the authors found increased survival in patients who received perioperative epidural analgesia and/or intraoperative dexamethasone. There was a 44% hazard ratio reduction, hazard ratio = 0.56, 95% confidence interval (0.38, 0.87), with dexamethasone. Adjuvant postoperative chemotherapy was associated with longer survival. A decrease in survival was noted in patients who received intraoperative blood transfusions, had poorer histologic grade, and advanced tumor stage. Conclusions: The authors report an association between perioperative dexamethasone administration and improved survival in human pancreatic adenocarcinoma patients. An association between use of epidural anesthesia during primary pancreatic cancer surgery and prolonged survival was also observed. Previously identified associations between perioperative blood transfusions and poor tumor histologic grade and decreased survival were confirmed. Further investigations regarding the use of perioperative dexamethasone and neuraxial anesthesia in this patient population are warranted.

Background and AimsGenes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) susceptibility have been shown to play a role in pancreatic cancer susceptibility. Germline genetic testing of pancreatic cancer cases could be beneficial for at-risk relatives with pathogenic variants in established HBOC and CRC genes, but it is unclear what proportion of pancreatic cancer cases harbor pathogenic variants in these genes.Methods66 pancreatic cancer cases, unselected for family history and diagnosed at the Huntsman Cancer Hospital (HCH), were sequenced on a custom 34-gene panel including known HBOC and CRC genes. A second set of 156 unselected HCH pancreatic cancer cases were sequenced on an expanded 59-gene panel (n=95) or with a custom 14-gene clinical panel (n=61). Sequencing data from both sets of pancreatic cancer cases, the pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and variants of uncertain significance.ResultsApproximately 8.9% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 10.5% carry a pathogenic variant or HiP-VUS.ConclusionWith the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases have a high enough percentage of carriers to rationalize genetic testing for identification of variants that could be further used in cascade testing of healthy relatives to increase HBOC and CRC surveillance measures.

Many patients with stage I-II pancreatic adenocarcinoma do not undergo resection. We hypothesized that (1) clinical staging underestimates nodal involvement, causing stage IIB to have a greater percent of resected patients and (2) this stage-shift causes discrepancies in observed survival.The Surveillance, Epidemiology, and End Results (SEER) research database was used to evaluate cause-specific survival in patients with pancreatic adenocarcinoma from 2004-2012. Survival was compared using the log-rank test. Single-center data on 105 patients who underwent resection of pancreatic adenocarcinoma without neoadjuvant treatment were used to compare clinical and pathologic nodal staging.In SEER data, medium-term survival in stage IIB was superior to IB and IIA, with median cause-specific survival of 14, 9, and 11 months, respectively (P .001). Seventy-two percent of stage IIB patients underwent resection vs 28% in IB and 36% in IIA (P .001). In our institutional data, 12.4% of patients had clinical evidence of nodal involvement vs 69.5% by pathologic staging (P .001). Among clinical stage IA-IIA patients, 71.6% had nodal involvement by pathologic staging.Both SEER and institutional data support substantial underestimation of nodal involvement by clinical staging. This finding has implications in decisions regarding neoadjuvant therapy and analysis of outcomes in the absence of pathologic staging.

The prognosis for patients with pancreatic cancer is extremely poor, as evidenced by the disease's five-year survival rate of ~5%. New approaches are therefore urgently needed to improve detection, treatment, and monitoring of pancreatic cancer. MRS-detectable metabolic changes provide useful biomarkers for tumor detection and response-monitoring in other cancers. The goal of this study was to identify MRS-detectable biomarkers of pancreatic cancer that could enhance currently available imaging approaches. We used (1) H high-resolution magic angle spinning MRS to probe metabolite levels in pancreatic tissue samples from mouse models and patients. In mice, the levels of lipids dropped significantly in pancreata with lipopolysaccharide-induced inflammation, in pancreata with pre-cancerous metaplasia (4 week old p48-Cre;LSL-Kras(G12D) mice), and in pancreata with pancreatic intraepithelial neoplasia, which precedes invasive pancreatic cancer (8 week old p48-Cre LSL-Kras(G12D) mice), to 26 ± 19% (p = 0.03), 19 ± 16% (p = 0.04), and 26 ± 10% (p = 0.05) of controls, respectively. Lactate and taurine remained unchanged in inflammation and in pre-cancerous metaplasia but increased significantly in pancreatic intraepithelial neoplasia to 266 ± 61% (p = 0.0001) and 999 ± 174% (p < 0.00001) of controls, respectively. Importantly, analysis of patient biopsies was consistent with the mouse findings. Lipids dropped in pancreatitis and in invasive cancer biopsies to 29 ± 15% (p = 0.01) and 26 ± 38% (p = 0.02) of normal tissue. In addition, lactate and taurine levels remained unchanged in inflammation but rose in tumor samples to 244 ± 155% (p = 0.02) and 188 ± 67% (p = 0.02), respectively, compared with normal tissue. Based on these findings, we propose that a drop in lipid levels could serve to inform on pancreatitis and cancer-associated inflammation, whereas elevated lactate and taurine could serve to identify the presence of pancreatic intraepithelial neoplasia and invasive tumor. Our findings may help enhance current imaging methods to improve early pancreatic cancer detection and monitoring.

BackgroundLength of stay (LoS) following elective surgery is being reported as an outcomes quality measure. Regional referral centres may care for patients travelling significant distances. The effect of travel distance on LoS in pancreatic surgery patients was examined.MethodsNational Surgical Quality Improvement Program data on pancreatic surgery patients, operated during the period from 2005 to 2011, were reviewed. Demographics, surgical variables and distance travelled were analysed relative to LoS. The LoS was log-transformed in general linear models to achieve normality.ResultsOf the 243 patients, 53% were male. The mean ± standard deviation (SD) age of the total patient sample was 60.6 ± 14 years. The mean ± SD distance travelled was 203 ± 319 miles (326.7 ± 513.4km) [median: 132 miles (212.4km); range: 3–3006 miles (4.8–4837.7km)], and the mean ± SD LoS was 10.5 ± 7 days (range: 1–46 days). Univariate analysis showed a near significant increase in LoS with increased distance travelled (P = 0.05). Significant variables related to LoS were: age (P = 0.002); relative value units (P < 0.001), and preoperative American Society of Anesthesiologists class (P = 0.005). In a general linear model, for every 100 miles (160.9km) travelled there is an associated 2% increase in LoS (P = 0.031). When the distance travelled is increased by 500 miles (804.7km), LoS increases by 10.5%.ConclusionsIncreased travel distance from a patient's home to the hospital was independently associated with an increase in LoS. If LoS is a reportable quality measure in pancreatic surgery, travel distance should be considered in risk adjustments.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 5%. There is an urgent need for early detection while the tumors are small and surgically resectable. We assessed serum osteopontin (OPN) and tissue inhibitor of metalloproteinase 1 (TIMP-1) as possible diagnostic and prognostic biomarkers in a novel cohort of patients with pancreatic cancer.Osteopontin and TIMP-1 levels were determined in sera from 86 patients with PDAC, 86 healthy control subjects, and 48 patients with chronic pancreatitis. Regression models were used to relate OPN and TIMP-1 to sex, age, stage, class, and treatment. Survival analyses were performed using univariate and multivariate Cox models.The serum levels of both OPN and TIMP-1 distinguished PDAC from chronic pancreatitis (P ≤ 0.0001) and healthy control subjects (P0.0001). The serum levels of both OPN and TIMP-1 also distinguished early-stage resectable PDAC cases from chronic pancreatitis (P0.04) and healthy control subjects (P0.01). High serum levels of OPN were significantly correlated with reduced patient survival.Serum OPN and TIMP-1 have use as diagnostic biomarkers in PDAC. Our data suggest a potential benefit of using OPN, TIMP-1, and CA 19-9 in a panel to improve diagnostic accuracy in PDAC.

Pancreatic cancer is the fourth most common cause of cancer mortality in the United States, with 5 year survival rates for patients with resectable tumors ranging from 15 - 20%. However, most patients present with distant metastases, are not resectable, and have a 5-year survival of close to 0%. This demonstrates a need for improved screening to identify pancreatic cancer while the tumor is localized and amenable to surgical resection. Studies of patients with pancreatic tumors incidentally diagnosed demonstrate longer median survival as compared with tumors discovered only when the patient is symptomatic, suggesting that early detection may improve outcome. Recent evidence from genomic sequencing indicates a 15 year interval for genetic progression of pancreatic cancer from initiation to the metastatic stage, suggesting a sufficient window for early detection. Still, many challenges remain in implementing effective screening. Early diagnosis of pancreatic cancer relies on developing screening methodologies with highly sensitive and specific biomarkers and imaging modalities. It also depends on a better understanding of the risk factors and natural history of the disease in order to accurately identify high risk groups that would be best served by screening. This review summarizes our current understanding of the biology of pancreatic cancer relevant to methods available for screening. At this time, given the lack of proven benefit in this disease, screening efforts should probably be undertaken in the context of prospective trials.

Proteomic analyses of readily obtained human fluids (e.g., serum, urine, and saliva) indicate that the diagnosis of complex diseases will be enhanced by the simultaneous measurement of multiple biomarkers from such samples. This paper describes the development of a nanoparticle-based multiplexed platform that has the potential for simultaneous read-out of large numbers of biomolecules. For this purpose, we have chosen pancreatic adenocarcinoma (PA) as a test bed for diagnosis and prognosis. PA is a devastating form of cancer in which an estimated 86% of diagnoses resulted in death in the United States in 2010. The high mortality rate is due, in part, to the asymptomatic development of the disease and the dearth of sensitive diagnostics available for early detection. One promising route lies in the development of a serum biomarker panel that can generate a signature unique to early stage PA. We describe the design and development of a proof-of-concept PA biomarker immunoassay array coupled with surface-enhanced Raman scattering (SERS) as a sensitive readout method.

BackgroundAfter acute necrotizing pancreatitis (ANP), a pancreatic fistula may occur from disconnected pancreatic duct syndrome (DPDS) where a segment of the pancreas is no longer in continuity with the main pancreatic duct.AimTo study the outcome of patients treated using Roux-Y pancreatic fistula tract-jejunostomy for DPDS after ANP.MethodsBetween 2002 and 2011, patients treated for DPDS in the setting of endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopanreatography (MRCP) documented main pancreatic duct disruption with Roux-Y pancreatic fistula tract-jejunostomy.ResultsIn all, seven patients with DPDS were treated. The median age was 62 years (range 49–78) and five were men. The cause of ANP was gallstones (2), alcohol (1), ERCP (1) and idiopathic (3). Pancreatic necrosectomy was done in six patients. Time from onset of pancreatitis to fistula drainage was 270 days (164–365). Pancreatic fistulae arose from DPDS in the head/neck (4) and body/tail (3). Patients had a median fistula output of 140ml (100–200) per day before surgery. The median operative time was 142min (75–367) and estimated blood loss was 150ml (25 to 500). Patients began an oral diet on post-operative day 4 (3–6) and were hospitalized for a median of 7 days (5–12). The median follow-up was 264 days (29–740). Subsequently, one patient required a distal pancreatectomy. After surgery, three patients required oral hypoglycaemics. No patient developed pancreatic exocrine insufficiency.ConclusionInternal surgical drainage using Roux-en-Y pancreatic fistula tract-jejunostomy is a safe and definitive treatment for patients with DPDS.

The aims of this study is to determine the maximum tolerated dose of capecitabine and oxaliplatin (CAPOX) delivered concurrent with radiation therapy (RT) in the treatment of locally advanced pancreatic adenocarcinoma and to retrospectively compare outcomes with this regimen to concurrent 5-fluorouracil or capecitabine with RT (5FU-RT) or concurrent gemcitabine-based chemotherapy with RT (GEM-RT).Twelve patients were enrolled in a phase I study using 50.4 Gy RT concurrent with capecitabine chemotherapy (twice daily, 7 days per week) and oxaliplatin (once weekly during weeks 1, 2, 4, and 5). Capecitabine and oxaliplatin doses were 400 mg/m(2) and 50 mg/m(2), respectively, at dose level 1; 600 mg/m(2) and 50 mg/m(2) at level 2; and 600 mg/m(2) and 60 mg/m(2) at level 3. A standard dose of gemcitabine was recommended following RT or following surgery (if done). The outcomes of patients treated with this regimen were retrospectively compared to 20 patients treated with 5FU-RT and 30 patients treated with GEM-RT.Dose level 3 was tolerated with acceptable toxicity. Survival in patients receiving CAPOX-RT did not differ from GEM-RT or 5FU-RT. Response of the primary tumor was observed in 38% of patients treated with CAPOX-RT, 31% of patients treated with 5FU-RT, and 66% of patients treated with GEM-RT (p = 0.03 GEM-RT versus 5FU-RT).CAPOX-RT has acceptable toxicity. A retrospective comparison shows higher response rate with GEM-RT versus 5FU-RT, but this difference did not translate into improvement in overall survival.

Background: Improved diagnostic, predictive, and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Platelet factor 4 (PF4) has been proposed as a diagnostic biomarker for PDAC. We assessed the diagnostic and prognostic potential of serum PF4 levels in PDAC patients. Methods: Serum PF4 levels were determined by enzyme-linked immunosorbent assay in an initial cohort of 62 PDAC patients, 62 healthy control subjects, and 34 chronic pancreatitis patients. A second validation set consisted of 71 PDAC patients. Linear regression models were used to relate PF4 to class, gender, age, stage, platelet count, and diagnosis. Survival analyses were done using univariate and multivariate Cox models. Results: In the initial cohort, serum PF4 levels distinguished PDAC from chronic pancreatitis patients (P = 0.011), but not from healthy control subjects (P = 0.624). In PDAC patients, high serum PF4 level significantly predicted decreased survival independent of all covariates examined (P < 0.01). The prognostic relationship of serum PF4 levels remained significant in the validation set. Venous thromboembolism (VTE) occurred in 20% of the 133 PDAC patients. The VTE risk was higher in subjects with elevated PF4 levels (P = 0.009). Conclusions: Serum PF4 is shown for the first time to be prognostic for survival in PDAC patients. High PF4 is associated with an increased risk for the development of VTE. Impact: Serum PF4 levels may be useful for patient stratification and for directing treatment options in patients with pancreatic cancer including anticoagulation prophylaxis. The relationship between high PF4 levels and poorer outcomes requires further study. Cancer Epidemiol Biomarkers Prev; 19(10); 2605–10. ©2010 AACR.

Several familial pancreatic cancer syndromes have been identified. However, the prevalence of familial pancreatic cancers in the general population has not been well defined.We linked pancreatic cancer cases, identified through the Utah Cancer Registry, to the Utah Population Database, which contains genealogic data from Utah pioneers and their descendants. This database includes 1411 pancreatic adenocarcinoma cases with 3 or more generations of Utah pioneer genealogy. We examined the familial clustering of pancreatic cancer by evaluating the relative risk (RR) of pancreatic cancer among relatives of cases. We also used the genealogical index of familiality to test the hypothesis of no excess relatedness among pancreatic cancer cases.The risk of pancreatic cancer was significantly increased in first-degree (RR, 1.84; 95% confidence interval [CI], 1.47-2.29; P.0001) and second-degree (RR, 1.59; 95% CI, 1.31-2.91; P.0001) relatives of individuals with pancreatic cancer. Analysis of case relatedness indicated significant excess relatedness for pancreatic cancer. More than 300 high-risk pedigrees were identified, with from 3-14 cases observed among descendants of pedigree founders.This population-based study provides evidence for increased risk of pancreatic cancer among relatives of cases and for a significantly higher average relatedness among cases than expected. These observations support the role of genetic factors in pancreatic cancer.

Pancreatic intraductal papillary mucinous neoplasms (IPMN) are cystic mucin-secreting tumors that arise within the pancreatic ductal system and are considered precursor lesions of pancreatic ductal adenocarcinoma. Profiling the immune infiltrate of IPMNs is essential to understand the immune mechanisms associated with the progression of IPMN. The aim of this study was to characterize the immune profiling of IPMN. We examined 31 formalin-fixed and paraffin-embedded tumor samples from surgically resected IPMN. The diagnostic slides were histologically reviewed by 2 expert pathologists in pancreas and classified as low-grade IPMN (low to intermediate grade dysplasia, N=11), high-grade IPMN (high grade dysplasia, N=18) and IPMN with invasive adenocarcinoma (N=2). Multiplex immunofluorescence (mIF) was used to characterize the immune profiling using two panels: Panel 1: PD-L1, PD1, CD3 (pan T cells), CD8 (T-cytotoxic), CD68 (macrophages), CK (AE1/AE3), DAPI. Panel 2: CD20 (B cells), CD45RO (T-memory), CD57 (NK), Granzyme B (NK and cytotoxic), FOXP3 (T reg), CK (AE1/AE3), DAPI. The slides were scanned using the Vectra multispectral microscope and analyzed by the InForm software (PerkinElmer). We quantified and co-localized immune phenotypes (epithelial cells PD-L1+; Total T-cell lymphocytes; T-cells antigen-experienced; Cytotoxic T-cells; Total macrophages; Macrophages PD-L1+; Total B-cell lymphocytes; Memory T cells; Granzyme B+ cells; Regulatory T cells; NK cells) in low grade dysplasia (LGD), high grade dysplasia (HGD), and invasive carcinoma areas in epithelial and stromal compartments. The Wilcoxon rank sum test or the Wilcoxon singed-rank test was used to test the equality of medians between two independent groups or paired samples, respectively. In all patients, HGD areas showed significantly higher density of macrophages (P= 0.041) and lower density of B-cell lymphocytes (P= 0.028) compared with LGD areas in the epithelial/stromal and epithelial compartments, respectively. Similar differences were observed when patients with high-grade IPMN (n=18) were analyzed for immune infiltrates in the HGD areas compared with LGD areas in the same tumor samples: HGD areas showed significantly higher density of macrophages (P= 0.035) and lower density of B-cell lymphocytes (P= 0.031). Patients with high-grade IPMN had significantly lower densities of B-cell lymphocytes (P= 0.011), T-cell lymphocytes (P= 0.034), and memory T-cells (P= 0.031) in the HGD areas when compared with LGD areas from patients with low-grade IPMN, in the epithelial compartment. No significant differences were found between LGD areas from patients who had high-grade IPMN and LGD areas from patients with low-grade IPMN. In conclusion, we characterized the immune landscape of IPMN and identified immune cell biomarkers associated with progression of IPMN. Citation Format: Luisa M. Solis, Naohiro Uraoka, Edwin Roger Parra, Yu Shen, Wei Wei, Mei Jiang, Barbara Mino, Kajsa Affolter, Courtney L. Scaife, Michele T. Yip-Schneider, C. Max Schmidt, Matthew Firpo, Sean Mulvihill, Eugene J. Koay,, Huamin Wang, Ignacio I. Wistuba, Anirban Maitra, Subrata Sen. Characterization of immune profiling of pancreatic intraductal papillary mucinous neoplasm using multiplex immunofluorescence and image analysis approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3121.

The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.

404 Background: Guidelines for adjuvant chemotherapy in patients with resected pancreatic adenocarcinoma (PDAC) who received neoadjuvant chemotherapy are equivocal. A lymph node ratio (LNR) ≥ 0.15 may predict lack of benefit, but conflicting results are reported. Methods: The National Cancer Database was searched to identify patients who were resected after neoadjuvant chemotherapy in 2006-2013. Exclusions: metastases at surgery, 90-day postoperative mortality, adjuvant radiation, and outlier interval from diagnosis to surgery (10 months). The association between adjuvant chemotherapy and overall survival (OS) from diagnosis was examined using multivariable Cox regression and inverse propensity of treatment weighted (IPTW) Cox regression. An IPTW based estimator of the average treatment effect (ATE) was used to quantify the population average survival benefit of treatment. Outcomes were examined in all patients and in those with LNR < 0.15 and ≥ 0.15. Results: 681/2488 patients (27%) received adjuvant chemotherapy. In multivariable Cox regression, adjuvant chemotherapy was associated with improved OS in the overall cohort and in patients with LNR < 0.15. A trend towards improved OS was also observed for those with LNR ≥ 0.15. After accounting for indication bias using IPTW, a significant survival benefit for was observed only for patients with LNR < 0.15. The ATE among LNR < 0.15 patients was 3.3 (95% CI 1.0, 5.7) months, indicating that the average survival of the population would be 3.3 months longer if all received treatment. Conclusions: Adjuvant chemotherapy in resected PDAC patients who received neoadjuvant therapy appears to be beneficial in patients with negative lymph nodes or minimal nodal burden. High LNR after neoadjuvant therapy may be an indicator of adverse tumor biology that is less likely to derive a therapeutic benefit. [Table: see text]

Timely, accurate diagnosis of pancreatic adenocarcinoma (PA) is hampered by the lack of effective circulating biomarkers. No single test has emerged that improves upon the commonly used biomarker cancer antigen 19–9 (CA 19–9) to discriminate PA from benign conditions effectively. The goals of this study were to validate two acute-phase proteins, haptoglobin and serum amyloid A (SAA), as biomarkers for PA and determine if the combination of haptoglobin, SAA, and CA 19–9 would improve PA diagnosis over CA 19–9 alone. Levels of haptoglobin, SAA, and CA 19–9 were measured in pretreatment sera from 75 PA patients, 32 patients with chronic pancreatitis, 42 patients with other benign pancreatic disease or biliary stricture, and 150 healthy control subjects by enzyme-linked immunosorbent assay or colorimetric binding assay. Relative levels of haptoglobin or SAA were compared between groups using analysis of variance. The diagnostic accuracy of serum haptoglobin and SAA levels were investigated using receiver operating characteristics (ROC) analysis. Using classification tree analysis, an algorithm was developed that used haptoglobin, SAA, and CA 19–9 in a diagnostic screening panel. Both haptoglobin and SAA were significantly elevated in sera from PA patients compared to healthy control subjects (p

Pancreatectomy is a high-risk, technically demanding operation associated with substantial perioperative morbidity and mortality. This study aims to describe the 30-day morbidity and mortality for pancreatectomy and to compare outcomes between private-sector and Veterans Affairs hospitals using multiinstitutional data.This is a retrospective review of patients who underwent pancreatic resection for neoplasia at private-sector (PS) and Veterans Affairs (VA) hospitals participating in the National Surgical Quality Improvement Program Patient Safety in Surgery Study in fiscal years 2002 to 2004. The variables reviewed were demographics, preoperative medical conditions, intraoperative variables, and outcomes. Using logistic regression to control for differences in patient comorbidities, 30-day mortality and morbidity rates between PS and VA hospitals were compared.A total of 1,069 patients underwent pancreatectomy for neoplasia at 97 participating hospitals. Six hundred ninety-two patients were treated at PS hospitals and 377 at VA hospitals. The average number of patients treated at each hospital was 11.0, with a range of 1 to 83 during the 3-year study period. There were 842 patients who underwent pancreaticoduodenectomy (CPT 4815x) and 227 who underwent distal/subtotal pancreatectomy (CPT 4814x). Significant differences were observed between PS patients and VA patients with regard to comorbidities and patient demographics. The 30-day unadjusted morbidity rate was 33.8% overall, 42.2% at VA hospitals versus 29.1% at PS hospitals (p0.0001). Unadjusted and adjusted odds ratio (OR) for postoperative morbidity comparing VA with PS hospitals was 1.781 (95% CI, 1.369-2.318) and 1.581 (95% CI, 1.064-2.307). The 30-day unadjusted operative mortality rate was 3.8% overall, 6.4% at VA hospitals and 2.5% at PS hospitals (p = 0.0015). Unadjusted and adjusted OR for postoperative mortality was 2.909 (95% CI, 1.525-5.549) and 2.533 (95% CI, 1.020-6.290), respectively. Similar outcomes were observed when looking at pancreaticoduodenectomy (CPT 4815x) when analyzed independent of other types of pancreatic resections.Pancreatectomies are high-risk operations with substantial perioperative morbidity and mortality. Risk-adjusted outcomes for patients treated at PS hospitals were found to be superior to those for patients treated at VA hospitals in the study.

Hepatocellular carcinoma (HCC) is the most common primary hepatic tumor and one of the most common cancers worldwide. At present, there are two widely used and accepted methods for obtaining diagnostic material for establishing the likelihood of malignancy in a hepatic mass, namely fine-needle aspiration (FNA) cytology and needle core biopsy (NCB). In recent years, however, tumor cell seeding along the needle tract has been shown to be a risk associated with using these procedures to obtain a pathologic diagnosis. We report a case of a patient who presented with a nodule in the anterior abdominal wall at the expected location of the previous NCB tract. FNA biopsy of the abdominal wall lesion confirmed the presence of malignant cells consistent with HCC. The finding of tumor seeding within a NCB tract raises the question of the role of NCB in the diagnostic workup of focal liver lesions.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

Delay in diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with decreased survival. The effect of an initial misdiagnosis on delay in diagnosis and stage of PDAC is unknown. This study is a retrospective review (2000–2010) from a University-based cancer center of new diagnoses of proximal PDAC. Of 313 patients, 98 (31.3 %) had an initial misdiagnosis. Misdiagnosed patients were younger, 62.8 ± 12.6 vs. 68.0 ± 10.1 (p